重组葡激酶静脉溶栓治疗对急性心肌梗死血小板活化的作用
|
摘要
目的:探讨重组葡激酶(r-SAK)在急性心肌梗死(AMI)溶栓治疗中对血小板活化作用。评价其治疗AMI的临床疗效。
方法:选择符合1979 年WHO 诊断标准,确诊为AMI 发病12 小时以内患者33例,随机分为治疗组(A 组,r-SAK 治疗17 例)和对照组(B 组,rt-PA 治疗16 例),正常组(C 组20 例)。测定A、B 两组溶栓治疗前、溶栓后2h 及C组血浆中血小板α-颗粒膜蛋白(GMP-140)、凝血酶-抗凝血酶复合物(TAT)含量及溶栓90min 后冠脉造影等相关指标。
结果:A、B 两组治疗前血浆中GMP-140、TAT 含量均高于C 组正常人。A、B两组治疗前血浆中GMP-140、TAT 含量比较无显著差异。A、B 两组治疗后2h血浆中GMP-140 均升高,B 组血浆中GMP-140 升高显著明显。A 组治疗后2h血浆中TAT 浓度升高不显著,B 组治疗后2h 血浆中TAT 浓度升高显著。A、B两组溶栓治疗后再通率无明显差异。两组治疗后1 周的并发症发生率比较有明显差异,其中脏器出血发生率A 组较B 组减少。
结论:AMI患者血浆中GMP-140和TAT升高,表明血小板活化增强和体内处于高凝状态。血小板活化存在于r-SAK和rt-PA溶栓治疗AMI过程中,为血栓前状态的主要机制之一。应用纤溶剂溶栓治疗中应加强抗血小板治疗。对于AMI患者应用r-SAK与rt-PA溶栓治疗有同等的溶栓疗效,r-SAK较后者有更强的血栓选择性,对促凝活性微弱,出血并发症发生率少,促血小板活化低,减轻血栓前状态对心肌损伤作用,可以改善心肌微灌注。
Acute myocardial infarction (AMI) is an emergency of cardio-vascular disease.Intracoronary thrombus formation is the most important pathogenetic mechanismin AMI. The most common cause of MI is rupture of an atherosclerotic plaque andthe formation of thrombus over the plaque resulting in rapid occlusion of the vessel.Occlusion thrombosis results in loss of blood flow to vital organs producing localoxygen deprivation, cell necrsis and loss of organ function. The most importanttherapeutic goal in the management of AMI is early restoration of complete infarctartery perfusion after the occlusion, which has been initiated with induced bythrombolytic therapy results in smaller infarct size, improving left ventricularfunction and reducing mortality. Thrombolysis has become routine therapy for AMIafter GISSI Trial. AMI has been dramatically changed by the advent ofthrombolytic treatment, with a 30% mortality reduction. This treatmentnotwithstanding, failure or delay in achieving reperfusion, less the tissue ofmyocardial reperfusion, along with reocclusion and severe hemorrhagiccomplication are the main unsolved problem of coronary thrombolysis. So arecombinant staphylokinase (r-SAK) is selected which had fibrinolysis functionand explored its thrombolytic efficacy and platelet activation of therapeuticconcentration.
Objection: To observe the effects in the vivo platelet activation parameters patientswith acute myocardial infarction of using r-SAK by intravenous thrombolysis,serial changes of the plasma concentration of thrombin-antithrombin complex(TAT), alpha granule membrane protein (GMP-140) and some other indexesconcentrations were measured before and at 2h after the administration of r-SAKand recombinant tissue-type plasminogen activators (rt-PA). So as to investigate theclinical thrombolytic efficacy of r-SAK therapy in AMI, comparing with rt-PAtherapy.
Methods: According to the criteria of AMI within 12h after the onset of symptoms diagnosisby WHO in 1979, 33 in-patients with AMI is selected (male 21 and 12 female, ageranged from 43-75, with mean age of 62.45±11.36 years), 33 patients were
divided into two groups randomly, the r-SAK therapy group (group A, 17cases) andthe rt-PA therapy group(group B, 16 cases). There were no differences between twogroups in general clinical conditions (Table2-5). Twenty healthy blood donors wereserved as controls (group C, 20cases). In group A we used r-SAK which wasobtained from Beijing Kendle Wits Medical Consulting Company, and In group Bwe used rt-PA, which was obtained from Boehringer Ingelheim, Ingelheim amRhein, Germany. Subsequently, all patients received aspirin 300mg and anintravenous bolus of heparin (5.000IU). Thrombolytic therapy was startedimmediately after the administration of the heparin bolus. The patients wererandomized to receive r-SAK, 2mg bolus over 2min followed by an additional 8mginfused over the first 30 min; rt-PA, 8mg bolus over 6min followed by an additional42mg infused over 90 min, immediately followed by a continuous intravenousinfusion of heparin (1.000 IU/h) which was then adjusted to maintain the activatedpartial thromboplastin time at >1.5 times baseline value. Coronary arteryangiography (CAG) was performed at 90 minutes after thrombolytic therapy inpatients. A baseline blood sample was obtained from enrolled patients before anytreatment was started. Group’s C blood samples came from the healthy blooddonors in blood bank of the Second Hospital, Jilin University. Additional bloodsamples were obtained at 2-h after the start of thrombolytic therapy. After the first3ml of blood was discarded, the 4ml venous samples were collected directly intocontaining an anticoagulant mixture composed of a thrombin inhibitor,ethylenediamineteraacetic acid (EDTA). The ratio of anticoagulant to blood was1:9 (vol/vol). All samples were immediately centrifuged at 4℃for 10 min at 3000r.The supernatant plasma was collected and frozen at -70℃until use. TAT andGMP-140 were measured by similar commercial enzyme-linked immunosorbentassay (ELISA). Reagent boxes of TAT and GMP-140’s were supplied with biologyproject research institute in Shanghai. Numerical variables data expressed as mean±SD. The variance and the Student t test were used to evaluate the difference incontinuous variables. The chi-square test was used to evaluate the difference incategorical variables. A p value<0.05 was considered statistically significant.Results: 1. In groups A and B, the baseline plasma levels of TAT and GMP-140 5
were significantly higher than group C (p<0.05). 2. In groups A and B, incomparison with baseline, at 2h after the start of thrombolytic therapy there was asignificant increase in the plasma concentration levels of GMP-140 (p<0.05). Ingroup B, the 2-h plasma levels of GMP-140 was significantly higher than baselinevalues (p<0.05). There was statistically significant in the 2-h plasma levels ofGMP-140 between groups A and B (p<0.05). 3. In groups A and B, in comparisonwith baseline, at 2-h t after the start of thrombolytic therapy here was an increase inthe plasma concentration levels of TAT. In group A, TAT plasma levels at 2-hdeterminations were no statistically significant in comparison with baseline(p>0.05). In group B, TAT plasma levels at 2-h determinations were statisticallysignificant in comparison with baseline (p<0.05). There were statisticallysignificant in the 2-h plasma levels of TAT between groups A and B (p<0.05). 4.There was no statistically significant of the reperfusion ratio at 2h after the start ofthrombolytic therapy between groups A and B (p>0.05). 5. There were statisticallysignificant in the complications incidence between the two treatment groups at 1week after the start of thrombolytic therapy (p<0.05). Bleeding complicationsincidence in the group A were less than those in the group B.Discussion: The study showed that the plasma concentration levels of TAT andGMP-140 increased in patients with AMI before the start of thrombolytic therapy.This reacted that in the vivo patients with AMI platelet activation and the activationof the hemostatic system increased, which was the same as reports of overseas andinterior[3]. The study showed that platelet activation and thrombin generation andactivity play a central role in the pathogenesis of coronary artery thrombosis andrethrombosis. There were no significant differences in the baseline plasmaconcentration levels of TAT between the two treatment groups. In groups A and B,in comparison with baseline, at 2-h after the start of thrombolytic therapy there wasan increase in the plasma concentration levels of TAT. In a pilot study, we alsoobserved a marked increase in both thrombin generation and activity in patientsreceiving thrombolytic therapy with rt-PA or streptokinase in the absence ofconcomitant anticoagulation with heparin. It is possible to speculate that at highrates of in vivo thrombin generation, as observed in patients with AMI, a
significant amount of factor Ⅹa is bound to activated platelet, thus allowing thisserine protease to resist the action of heparin. In addition, the direct activation ofplatelet and factor Ⅴa during thrombolysis, as well as the reexposure of theruptured plaque to blood flow, might lead to the generation of more factor Ⅹa and,consequently, to thrombin generation. The increase in prothrombin fragment 1+2and thrombin-antithrombin complex plasma levels in the first hours after theinitiation of thrombolysis despite heparin treatment further supports this hypothesis[63]. In group A, TAT plasma levels at 2-h determinations were no statisticallysignificant in comparison with baseline. Okada k et al. has showed that there wereless procoagulant properties during thrombolysis with r-SAK and it holds highlyfibrin-selective thrombolytic therapy [64]. The promotion of prothrombotis state wasdecreased. This experiment showed that between groups A and B in comparisonwith baseline, at 2h after the start of thrombolytic therapy there was a significantincrease in the plasma concentration levels of GMP-140. Platelets play a pivotalrole in these events through different mechanisms, and among these mechanismsare platelet interactions with physiologic fibrinolysis and pharmacologicthrombolysis. Patelet actively contribut to fibrinolysis because that they havespecific binding sites for plasminogen. Thrombolytic agents may modify plateletreactivity. Actually, platelet activation rate of platelet-bound plasminogen byplasmin is about one order of magnitude greater than that of free plasminogen. Onthe other hand, thrombolytic agents may modify platelet reactivity. Platelet may beactivated at the site of thrombolysis by plasmin or by the continued formation ofthrombin. Low plasmin concentrations may inhibit platelet activation whatever themechanism of platelet activation during coronary thrombolysis, the reduction inPGI2 biosynthesis in patients who reperfusion may further amplify plateletactivation in the setting. The loss of PGI2 formation may allow platelet activation tooccur in the reperfused the injured vascular bed and endothelial[65]. In group B, the2-h plasma levels of GMP-140 was significantly higher than baseline values.Fibrinolysis agents induced the effect of platelet activation mainly becausefibrinolysis agents appear to induce an activation of the platelet fibrinogen receptor,which is essential for platelet-platelet and platelet-subendothelium interactions,
方法:选择符合1979 年WHO 诊断标准,确诊为AMI 发病12 小时以内患者33例,随机分为治疗组(A 组,r-SAK 治疗17 例)和对照组(B 组,rt-PA 治疗16 例),正常组(C 组20 例)。测定A、B 两组溶栓治疗前、溶栓后2h 及C组血浆中血小板α-颗粒膜蛋白(GMP-140)、凝血酶-抗凝血酶复合物(TAT)含量及溶栓90min 后冠脉造影等相关指标。
结果:A、B 两组治疗前血浆中GMP-140、TAT 含量均高于C 组正常人。A、B两组治疗前血浆中GMP-140、TAT 含量比较无显著差异。A、B 两组治疗后2h血浆中GMP-140 均升高,B 组血浆中GMP-140 升高显著明显。A 组治疗后2h血浆中TAT 浓度升高不显著,B 组治疗后2h 血浆中TAT 浓度升高显著。A、B两组溶栓治疗后再通率无明显差异。两组治疗后1 周的并发症发生率比较有明显差异,其中脏器出血发生率A 组较B 组减少。
结论:AMI患者血浆中GMP-140和TAT升高,表明血小板活化增强和体内处于高凝状态。血小板活化存在于r-SAK和rt-PA溶栓治疗AMI过程中,为血栓前状态的主要机制之一。应用纤溶剂溶栓治疗中应加强抗血小板治疗。对于AMI患者应用r-SAK与rt-PA溶栓治疗有同等的溶栓疗效,r-SAK较后者有更强的血栓选择性,对促凝活性微弱,出血并发症发生率少,促血小板活化低,减轻血栓前状态对心肌损伤作用,可以改善心肌微灌注。
Acute myocardial infarction (AMI) is an emergency of cardio-vascular disease.Intracoronary thrombus formation is the most important pathogenetic mechanismin AMI. The most common cause of MI is rupture of an atherosclerotic plaque andthe formation of thrombus over the plaque resulting in rapid occlusion of the vessel.Occlusion thrombosis results in loss of blood flow to vital organs producing localoxygen deprivation, cell necrsis and loss of organ function. The most importanttherapeutic goal in the management of AMI is early restoration of complete infarctartery perfusion after the occlusion, which has been initiated with induced bythrombolytic therapy results in smaller infarct size, improving left ventricularfunction and reducing mortality. Thrombolysis has become routine therapy for AMIafter GISSI Trial. AMI has been dramatically changed by the advent ofthrombolytic treatment, with a 30% mortality reduction. This treatmentnotwithstanding, failure or delay in achieving reperfusion, less the tissue ofmyocardial reperfusion, along with reocclusion and severe hemorrhagiccomplication are the main unsolved problem of coronary thrombolysis. So arecombinant staphylokinase (r-SAK) is selected which had fibrinolysis functionand explored its thrombolytic efficacy and platelet activation of therapeuticconcentration.
Objection: To observe the effects in the vivo platelet activation parameters patientswith acute myocardial infarction of using r-SAK by intravenous thrombolysis,serial changes of the plasma concentration of thrombin-antithrombin complex(TAT), alpha granule membrane protein (GMP-140) and some other indexesconcentrations were measured before and at 2h after the administration of r-SAKand recombinant tissue-type plasminogen activators (rt-PA). So as to investigate theclinical thrombolytic efficacy of r-SAK therapy in AMI, comparing with rt-PAtherapy.
Methods: According to the criteria of AMI within 12h after the onset of symptoms diagnosisby WHO in 1979, 33 in-patients with AMI is selected (male 21 and 12 female, ageranged from 43-75, with mean age of 62.45±11.36 years), 33 patients were
divided into two groups randomly, the r-SAK therapy group (group A, 17cases) andthe rt-PA therapy group(group B, 16 cases). There were no differences between twogroups in general clinical conditions (Table2-5). Twenty healthy blood donors wereserved as controls (group C, 20cases). In group A we used r-SAK which wasobtained from Beijing Kendle Wits Medical Consulting Company, and In group Bwe used rt-PA, which was obtained from Boehringer Ingelheim, Ingelheim amRhein, Germany. Subsequently, all patients received aspirin 300mg and anintravenous bolus of heparin (5.000IU). Thrombolytic therapy was startedimmediately after the administration of the heparin bolus. The patients wererandomized to receive r-SAK, 2mg bolus over 2min followed by an additional 8mginfused over the first 30 min; rt-PA, 8mg bolus over 6min followed by an additional42mg infused over 90 min, immediately followed by a continuous intravenousinfusion of heparin (1.000 IU/h) which was then adjusted to maintain the activatedpartial thromboplastin time at >1.5 times baseline value. Coronary arteryangiography (CAG) was performed at 90 minutes after thrombolytic therapy inpatients. A baseline blood sample was obtained from enrolled patients before anytreatment was started. Group’s C blood samples came from the healthy blooddonors in blood bank of the Second Hospital, Jilin University. Additional bloodsamples were obtained at 2-h after the start of thrombolytic therapy. After the first3ml of blood was discarded, the 4ml venous samples were collected directly intocontaining an anticoagulant mixture composed of a thrombin inhibitor,ethylenediamineteraacetic acid (EDTA). The ratio of anticoagulant to blood was1:9 (vol/vol). All samples were immediately centrifuged at 4℃for 10 min at 3000r.The supernatant plasma was collected and frozen at -70℃until use. TAT andGMP-140 were measured by similar commercial enzyme-linked immunosorbentassay (ELISA). Reagent boxes of TAT and GMP-140’s were supplied with biologyproject research institute in Shanghai. Numerical variables data expressed as mean±SD. The variance and the Student t test were used to evaluate the difference incontinuous variables. The chi-square test was used to evaluate the difference incategorical variables. A p value<0.05 was considered statistically significant.Results: 1. In groups A and B, the baseline plasma levels of TAT and GMP-140 5
were significantly higher than group C (p<0.05). 2. In groups A and B, incomparison with baseline, at 2h after the start of thrombolytic therapy there was asignificant increase in the plasma concentration levels of GMP-140 (p<0.05). Ingroup B, the 2-h plasma levels of GMP-140 was significantly higher than baselinevalues (p<0.05). There was statistically significant in the 2-h plasma levels ofGMP-140 between groups A and B (p<0.05). 3. In groups A and B, in comparisonwith baseline, at 2-h t after the start of thrombolytic therapy here was an increase inthe plasma concentration levels of TAT. In group A, TAT plasma levels at 2-hdeterminations were no statistically significant in comparison with baseline(p>0.05). In group B, TAT plasma levels at 2-h determinations were statisticallysignificant in comparison with baseline (p<0.05). There were statisticallysignificant in the 2-h plasma levels of TAT between groups A and B (p<0.05). 4.There was no statistically significant of the reperfusion ratio at 2h after the start ofthrombolytic therapy between groups A and B (p>0.05). 5. There were statisticallysignificant in the complications incidence between the two treatment groups at 1week after the start of thrombolytic therapy (p<0.05). Bleeding complicationsincidence in the group A were less than those in the group B.Discussion: The study showed that the plasma concentration levels of TAT andGMP-140 increased in patients with AMI before the start of thrombolytic therapy.This reacted that in the vivo patients with AMI platelet activation and the activationof the hemostatic system increased, which was the same as reports of overseas andinterior[3]. The study showed that platelet activation and thrombin generation andactivity play a central role in the pathogenesis of coronary artery thrombosis andrethrombosis. There were no significant differences in the baseline plasmaconcentration levels of TAT between the two treatment groups. In groups A and B,in comparison with baseline, at 2-h after the start of thrombolytic therapy there wasan increase in the plasma concentration levels of TAT. In a pilot study, we alsoobserved a marked increase in both thrombin generation and activity in patientsreceiving thrombolytic therapy with rt-PA or streptokinase in the absence ofconcomitant anticoagulation with heparin. It is possible to speculate that at highrates of in vivo thrombin generation, as observed in patients with AMI, a
significant amount of factor Ⅹa is bound to activated platelet, thus allowing thisserine protease to resist the action of heparin. In addition, the direct activation ofplatelet and factor Ⅴa during thrombolysis, as well as the reexposure of theruptured plaque to blood flow, might lead to the generation of more factor Ⅹa and,consequently, to thrombin generation. The increase in prothrombin fragment 1+2and thrombin-antithrombin complex plasma levels in the first hours after theinitiation of thrombolysis despite heparin treatment further supports this hypothesis[63]. In group A, TAT plasma levels at 2-h determinations were no statisticallysignificant in comparison with baseline. Okada k et al. has showed that there wereless procoagulant properties during thrombolysis with r-SAK and it holds highlyfibrin-selective thrombolytic therapy [64]. The promotion of prothrombotis state wasdecreased. This experiment showed that between groups A and B in comparisonwith baseline, at 2h after the start of thrombolytic therapy there was a significantincrease in the plasma concentration levels of GMP-140. Platelets play a pivotalrole in these events through different mechanisms, and among these mechanismsare platelet interactions with physiologic fibrinolysis and pharmacologicthrombolysis. Patelet actively contribut to fibrinolysis because that they havespecific binding sites for plasminogen. Thrombolytic agents may modify plateletreactivity. Actually, platelet activation rate of platelet-bound plasminogen byplasmin is about one order of magnitude greater than that of free plasminogen. Onthe other hand, thrombolytic agents may modify platelet reactivity. Platelet may beactivated at the site of thrombolysis by plasmin or by the continued formation ofthrombin. Low plasmin concentrations may inhibit platelet activation whatever themechanism of platelet activation during coronary thrombolysis, the reduction inPGI2 biosynthesis in patients who reperfusion may further amplify plateletactivation in the setting. The loss of PGI2 formation may allow platelet activation tooccur in the reperfused the injured vascular bed and endothelial[65]. In group B, the2-h plasma levels of GMP-140 was significantly higher than baseline values.Fibrinolysis agents induced the effect of platelet activation mainly becausefibrinolysis agents appear to induce an activation of the platelet fibrinogen receptor,which is essential for platelet-platelet and platelet-subendothelium interactions,
引文
1.Herrick JB. Clinical features of sudden obstruction of the coronary arteries[J].JAMA.1912,59:2015-2020
2.DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden ms, Lang HT, Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction[J]. N Engl J Med.1980,303:897-902
3.金兰,张抒扬,严晓伟,等。急性心肌梗塞患者溶栓治疗期间纤溶活性和血小板功能的变化及其临床意义[J].中华心血管病杂志,1995,23(4):261-263
4.Gruppo Italiano per Io Studio della Streptochinasi nell’Infarto Miocardico ( GISSI ) .Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction[J]. Lancet.1986,1:397-402
5.朱文玲.急性心肌梗死再灌注治疗的循证医学[J]. 中国循环杂志,2003,18 (1):64-66
6.Takada A, Takada Y, Utano T. The physiological aspects of fibrinolysis [J]. Thromb Res.1994, 76: 1
7.Owen J, Friedman KD, Grossman BA .et al. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity [J]. Blood,1988,72:616
8.Bleich SD, Nichols TC, Schumacher RR, et al. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction[J]. Am J Cardiol,1990, 66:1412
9.Hsia J, Hamilton WP, Kleiman N, et al. for the Heparin Aspirin Reperfusion Trial(HART)Investigators: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction[J]. N Engl J Med ,1990, 323:1433
10.De Bono DP, Simoons ML, Tijssen J, et al. for the European Cooperative Study Group (ECSG): Effect of early intravenous heparin on coronary patency, infarc size and bleeding complications after alteplase thrombolysis: Results of a randomised double blind European Cooperative Study Group trial[J]. Br Heart J,1992,67:122
11.李春坚,黄峻.葡激酶的研究进展[J],心血管病学进展,2002,23(2): 110-113
12.张连峰,李锦堂,韩崇旭,等.缺血性心脏病和脑血管疾病血浆中GMP-140 的变化[J].中华血液学杂志,1995,16(9):485
13.Corash L. Measurement of platelet activation by fluorescence activated flow cytometry [J]. Blood Cell,1999,16:97
14.Nurden AT, Bihour C, Macchi L, et al. Platelet activation in thrombotic disorders [J]. Nouv Rev Fr Hematol, 1993,35(1): 67
15.Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S.The treatment of patients suffering from early myocardial infarction with assive and prolonged streptokinase therapy[J]. Trans Assoc Am Physicians.1958, 71:287-296
16.Raimania G,Vesterqvint Q,Green K,et al. Evidence of increased platelet activation after thrombolysis impatients with myocardial infarction [J].Br Heart J,1992,68(4):374-376
17.吴方,王学锋,曾晓颖,等. 高凝状态患者止凝血分子标志物的检测及临床意义[J].上海医学检验杂志,2000,15(3):180-182
18.Coller BS: Platelets and thrombolytic therapy[J]. N Engl J Med, 1990:322-33
19.ISIS-2(Second International Study of Infarct Survival Collaborative Group).Randomised trial of intravenous streptokinase,oral aspirin, both,or neither among 17 187cases of suspected acute myocardial infarction:ISIS-2 [J].Lancet,1988,2:49-360
20.The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator,streptokinase,or both on coronary-artery patency. ventricular function,and survival after acute myocardialinfarction [published erratum appears in N Engl J Med. 1994,330: 516][J].N Engl J Med. 1993,329:1615-1622
21.Smalling RW,Bode C,Kalbfleiach J,et al. for the RAPID Investigators. More rapid,complete,and stable coronary thrombolysis with bolus adminlis-tration of reteplase compared with alteplase infusion in acute myocardial infarction[J]. Circulation,1995,91:2725-2732
22.GUSTO-3 Investigator. An international, multicenter, randomized comparison of reteplase for acute myocardial infarction [J]. N Engl J Med, 1997,337:1118-1123
23.Shab A,Wagner GS,Grange CB,et al.for Reexamining the “Gold Standard ”for myocardial reperfusion assegament , prognosine implication of TIMI flow grade in the infarct related artery compared with continuous 12-lead ST-segment resolution analysis[J],J Am Cool Cardiol,2000;35:666-672
24.Ito H,Tomooke T,Sakai N,et al. Lack of myocardial perfusion immediately after successful thrombolysis,A predictor of recovery of left ventricular function in anterior myocardial infarction[J], Circulation,1992,85:1699-1705
25.Kloner RA,Ganote CE,Jenning RB,et al. The“no reflow”phenomenon after temporary coronary occlusion in the dog[J], J Clin Invest, 1974,54:1496-1508
26.Kloner RA,Rude RE, Carlson N,et al. Ultrastructucal evidence of microvascular damage and myocardial cell injury after coronary artery occlusion:Which comes first [J]? Circulation,1980,62:945-952
27.TopolEJ.Coronary disease:acute myocardial infarction thrombolysis [J].Heart,2000,83:122-126
28.刘刚,沈洪,畅坚等. 家兔股浅动脉血栓溶解后微小血管栓塞对组织再灌 注的影响[J]. 中国急救医学,2003, 23(2):74-76
29.刘刚,沈洪.急性心肌梗死溶栓治疗后的微血栓问题[J].中国危重病急救医 学,2002,14(4):255
30.黄从新.急性心肌梗死溶栓治疗的最新进展[J],中国实用内科杂志,2003, 23(8):449
31.Lack CH. Staphylokinase:an activator of plasm a rotease [J]. Nature, 1948,161:559-560
32.Sako T, Sawaki T, Ito S, et al. Cloning and expression of staphylokinase gene of Staphylococcus aureus in Escherichia coli [J]. Mol Gen Genet,1983,190:271-277
33.桂向东,吴清发,范清林,等.葡萄球菌激酶的基因克隆和高效表达工程菌的 构建[J].生物学杂志,1998,15(4):12-14
34.汤其群,张小璇,于敏,等.重组葡激酶的分离、纯化和结晶[J].药物生物 技术,1997,4(1):1-4
35.Rabijins A, De Bondt HL, DeRanter C. Three-dimensional structure of staphylokinase, a plasminogen activator with therapeutic potential [J]. Nature Structure Biology, 1997,4:357
36.Ohlenschlager O, Ramachandran R, Guhrs KH. Nuclear magnetic resonance solution structure of the plasminogen-activator protein staphylofinae[J]. Biochemistry ,1998,28,37(30): 10635
37.Sako T , Sawaki T , Ito S , et al. Cloning and expression of staphylokinaes gene of staphylococuse aureus in Escherichia coli[J]. Mole Gen Genal,1983,190:271-277
38.Behnke D, Gerlach D. Cloning and expression in Escherichia coli, Bacillus subtilis, and Streptococcus sanguis of a gene for staphylokinase, a bacterial plasminogen activator[J]. Mol Gen Genet,1987,210:528-534
39.Collen D, Silence K, Demarsin E, et al. Isolation and characterization of natural and recombinant staphylokinase [J]. Fibrinolysis,1992,6:203-213
40.Collen D, Schlott B, Engelborghs Y, et al. On the mechanism of the activation of human plasminogen by recombinant staphylokinase[J]. J Biol Chem, 1993, 268 (11): 8284-8289
41.Lijnen HR, Van Hoef B, Collen D. Interaction of staphylokinase with different molecular forms of plasminogen [J]. Eur J Biochem, 1993, 211(1-2): 91-97
42.Silence K, Collen D, Lijnen HR. Interaction between staphylokinase, plasminogen, and alpha2-antiplasmin. Recycling of staphylokinase after neutralization of the plasmin staphylokinase complex by alpha2-antiplas min [J]. J Biol Chem, 1993,268 (13):9811–9816
43.Lijnen HR, van Hoef B, Matsuo O, et al. On the molecular interaction between plasminogen staphylokinase , alpha2-antiplasmin and fibrin[J].Biochim Biophys Acta,1992,1118(2):144-148
44.Vanderschueren S, Dens J, Kerdsinchai P, et al. Randomized coronary patency trial of double –bolus recombinant staphylokinase versus front –loaded alteplase in acute myocardial infarction [J]. Am Heart J,1997,134:213-219
45.Suehiro A, Tsujioka H, Yoshimoto H, et al. Enhancing effect of platelets on staphylokinase mediated clotlysis and plasminogen activation [J]. Thromb Res,1995,80(2):135-142
46.Suehiro A, Oura Y, Ueda M, et al. Inhibitory effect of staphylokinase on platelet aggregation [J]. Thromb Haemost,1993,70(5):834-83747.Collen D, vandeWerf F. Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction [J]. Circulation,1993,87(6):1850-1853
48.Shishido Y, Matsumoto T, Sakai M, et al. Fibrin specific fibrinolysis induced by recombinant staphylokinase [J]. Biol Pharm Bull, 1994, 17(8):1060-1064
49.Vanderschueren S, vanVlaenderen I, Collen D. Intravenous thrombolysis with recombinant staphylokinase versus tissue-type plasminogen activator in a rabbit embolic stroke model [J]. Stroke, 1997,28(9):1783-1788
50.Lijnen HR, Stassen JM, Vanlinthout I, et al. Comparative fibrinolytic properties of staphylokinase in animal models of venous thrombosis [J]. Thromb Haemost,1991,66(4):468-473
51.Vanderschueren S, Barrios L, Kerdsinchai P, et al. A randomized trial of recombinant staphylokinase versus alteplase for coronary 27 artery patency in acute myocardial infarction. The STAR Trial Group
[J]. Circulation, 1995, 92(8):2044-2049
52.Fitzerald DJ, Roy L, Catella F, et al. Platelet activation in unstable coronary disease [J]. N Engl Med,1986,315:983-986
53.李海乾,王兆钺,阮长耿. 血小板凝血酶受体[J].国外医学·生理、病理 科学与临床分册,2002,20(1):4-6
54.耿美容,辛晓敏.TAT和GMP-140在急性心肌梗塞患者溶栓治疗中的应用价值 [J].哈尔滨医科大学学报,2003,37(3):257-259
55.刘汉,景本年,李卓江.血栓前状态分子标志物研究进展[J]. 国外医学临 床生物化学与检验学分册,2000,21(5):239-240
56.Lucia G,Piet WM,Albert EG,et al. P selection dependent adhesion of activation platelets to many different types of leukocytes detection by flow cytometry [J],Blood,1992,80:134
57.Mcever RP. The clinical significance of platelet menbrane grycoproteins Hematology/ oncology[J].Clin North Am,1990,4(1):87
58.Stenberg PE, McEver RP, Shuman MA, et al. A platelet plasma after activation [J].J Cell Biol,1985;101(3): 880-884
59.Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI,a thrombin-activable fibrinolysis inhibitor [J]. J Biol Chem, 1995,270:14477-14484
60.王鸿利,李建新,陈红兵.凝血酶-抗凝血酶和纤溶酶-抗纤溶酶复合物的检 测及临床应用[J].中国实验诊断学,2001,5(5):211-213
61.李家增,贺石林,王鸿利.血栓病[M].北京:科学出版社,1998,161-200; 308-434
62. Gulba DC, Daniel WG, Simon R, et al. Role of thrombosis and thrombin in the patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty[J]. J Am Coll Cardiol, 1999,16(3): 563-72
63.Merlini PA, Bauer KA, Oltrona L, et al. Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction [J]. J Am Coll Cardial,
2.DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden ms, Lang HT, Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction[J]. N Engl J Med.1980,303:897-902
3.金兰,张抒扬,严晓伟,等。急性心肌梗塞患者溶栓治疗期间纤溶活性和血小板功能的变化及其临床意义[J].中华心血管病杂志,1995,23(4):261-263
4.Gruppo Italiano per Io Studio della Streptochinasi nell’Infarto Miocardico ( GISSI ) .Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction[J]. Lancet.1986,1:397-402
5.朱文玲.急性心肌梗死再灌注治疗的循证医学[J]. 中国循环杂志,2003,18 (1):64-66
6.Takada A, Takada Y, Utano T. The physiological aspects of fibrinolysis [J]. Thromb Res.1994, 76: 1
7.Owen J, Friedman KD, Grossman BA .et al. Thrombolytic therapy with tissue plasminogen activator or streptokinase induces transient thrombin activity [J]. Blood,1988,72:616
8.Bleich SD, Nichols TC, Schumacher RR, et al. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction[J]. Am J Cardiol,1990, 66:1412
9.Hsia J, Hamilton WP, Kleiman N, et al. for the Heparin Aspirin Reperfusion Trial(HART)Investigators: A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction[J]. N Engl J Med ,1990, 323:1433
10.De Bono DP, Simoons ML, Tijssen J, et al. for the European Cooperative Study Group (ECSG): Effect of early intravenous heparin on coronary patency, infarc size and bleeding complications after alteplase thrombolysis: Results of a randomised double blind European Cooperative Study Group trial[J]. Br Heart J,1992,67:122
11.李春坚,黄峻.葡激酶的研究进展[J],心血管病学进展,2002,23(2): 110-113
12.张连峰,李锦堂,韩崇旭,等.缺血性心脏病和脑血管疾病血浆中GMP-140 的变化[J].中华血液学杂志,1995,16(9):485
13.Corash L. Measurement of platelet activation by fluorescence activated flow cytometry [J]. Blood Cell,1999,16:97
14.Nurden AT, Bihour C, Macchi L, et al. Platelet activation in thrombotic disorders [J]. Nouv Rev Fr Hematol, 1993,35(1): 67
15.Fletcher AP, Alkjaersig N, Smyrniotis FE, Sherry S.The treatment of patients suffering from early myocardial infarction with assive and prolonged streptokinase therapy[J]. Trans Assoc Am Physicians.1958, 71:287-296
16.Raimania G,Vesterqvint Q,Green K,et al. Evidence of increased platelet activation after thrombolysis impatients with myocardial infarction [J].Br Heart J,1992,68(4):374-376
17.吴方,王学锋,曾晓颖,等. 高凝状态患者止凝血分子标志物的检测及临床意义[J].上海医学检验杂志,2000,15(3):180-182
18.Coller BS: Platelets and thrombolytic therapy[J]. N Engl J Med, 1990:322-33
19.ISIS-2(Second International Study of Infarct Survival Collaborative Group).Randomised trial of intravenous streptokinase,oral aspirin, both,or neither among 17 187cases of suspected acute myocardial infarction:ISIS-2 [J].Lancet,1988,2:49-360
20.The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator,streptokinase,or both on coronary-artery patency. ventricular function,and survival after acute myocardialinfarction [published erratum appears in N Engl J Med. 1994,330: 516][J].N Engl J Med. 1993,329:1615-1622
21.Smalling RW,Bode C,Kalbfleiach J,et al. for the RAPID Investigators. More rapid,complete,and stable coronary thrombolysis with bolus adminlis-tration of reteplase compared with alteplase infusion in acute myocardial infarction[J]. Circulation,1995,91:2725-2732
22.GUSTO-3 Investigator. An international, multicenter, randomized comparison of reteplase for acute myocardial infarction [J]. N Engl J Med, 1997,337:1118-1123
23.Shab A,Wagner GS,Grange CB,et al.for Reexamining the “Gold Standard ”for myocardial reperfusion assegament , prognosine implication of TIMI flow grade in the infarct related artery compared with continuous 12-lead ST-segment resolution analysis[J],J Am Cool Cardiol,2000;35:666-672
24.Ito H,Tomooke T,Sakai N,et al. Lack of myocardial perfusion immediately after successful thrombolysis,A predictor of recovery of left ventricular function in anterior myocardial infarction[J], Circulation,1992,85:1699-1705
25.Kloner RA,Ganote CE,Jenning RB,et al. The“no reflow”phenomenon after temporary coronary occlusion in the dog[J], J Clin Invest, 1974,54:1496-1508
26.Kloner RA,Rude RE, Carlson N,et al. Ultrastructucal evidence of microvascular damage and myocardial cell injury after coronary artery occlusion:Which comes first [J]? Circulation,1980,62:945-952
27.TopolEJ.Coronary disease:acute myocardial infarction thrombolysis [J].Heart,2000,83:122-126
28.刘刚,沈洪,畅坚等. 家兔股浅动脉血栓溶解后微小血管栓塞对组织再灌 注的影响[J]. 中国急救医学,2003, 23(2):74-76
29.刘刚,沈洪.急性心肌梗死溶栓治疗后的微血栓问题[J].中国危重病急救医 学,2002,14(4):255
30.黄从新.急性心肌梗死溶栓治疗的最新进展[J],中国实用内科杂志,2003, 23(8):449
31.Lack CH. Staphylokinase:an activator of plasm a rotease [J]. Nature, 1948,161:559-560
32.Sako T, Sawaki T, Ito S, et al. Cloning and expression of staphylokinase gene of Staphylococcus aureus in Escherichia coli [J]. Mol Gen Genet,1983,190:271-277
33.桂向东,吴清发,范清林,等.葡萄球菌激酶的基因克隆和高效表达工程菌的 构建[J].生物学杂志,1998,15(4):12-14
34.汤其群,张小璇,于敏,等.重组葡激酶的分离、纯化和结晶[J].药物生物 技术,1997,4(1):1-4
35.Rabijins A, De Bondt HL, DeRanter C. Three-dimensional structure of staphylokinase, a plasminogen activator with therapeutic potential [J]. Nature Structure Biology, 1997,4:357
36.Ohlenschlager O, Ramachandran R, Guhrs KH. Nuclear magnetic resonance solution structure of the plasminogen-activator protein staphylofinae[J]. Biochemistry ,1998,28,37(30): 10635
37.Sako T , Sawaki T , Ito S , et al. Cloning and expression of staphylokinaes gene of staphylococuse aureus in Escherichia coli[J]. Mole Gen Genal,1983,190:271-277
38.Behnke D, Gerlach D. Cloning and expression in Escherichia coli, Bacillus subtilis, and Streptococcus sanguis of a gene for staphylokinase, a bacterial plasminogen activator[J]. Mol Gen Genet,1987,210:528-534
39.Collen D, Silence K, Demarsin E, et al. Isolation and characterization of natural and recombinant staphylokinase [J]. Fibrinolysis,1992,6:203-213
40.Collen D, Schlott B, Engelborghs Y, et al. On the mechanism of the activation of human plasminogen by recombinant staphylokinase[J]. J Biol Chem, 1993, 268 (11): 8284-8289
41.Lijnen HR, Van Hoef B, Collen D. Interaction of staphylokinase with different molecular forms of plasminogen [J]. Eur J Biochem, 1993, 211(1-2): 91-97
42.Silence K, Collen D, Lijnen HR. Interaction between staphylokinase, plasminogen, and alpha2-antiplasmin. Recycling of staphylokinase after neutralization of the plasmin staphylokinase complex by alpha2-antiplas min [J]. J Biol Chem, 1993,268 (13):9811–9816
43.Lijnen HR, van Hoef B, Matsuo O, et al. On the molecular interaction between plasminogen staphylokinase , alpha2-antiplasmin and fibrin[J].Biochim Biophys Acta,1992,1118(2):144-148
44.Vanderschueren S, Dens J, Kerdsinchai P, et al. Randomized coronary patency trial of double –bolus recombinant staphylokinase versus front –loaded alteplase in acute myocardial infarction [J]. Am Heart J,1997,134:213-219
45.Suehiro A, Tsujioka H, Yoshimoto H, et al. Enhancing effect of platelets on staphylokinase mediated clotlysis and plasminogen activation [J]. Thromb Res,1995,80(2):135-142
46.Suehiro A, Oura Y, Ueda M, et al. Inhibitory effect of staphylokinase on platelet aggregation [J]. Thromb Haemost,1993,70(5):834-83747.Collen D, vandeWerf F. Coronary thrombolysis with recombinant staphylokinase in patients with evolving myocardial infarction [J]. Circulation,1993,87(6):1850-1853
48.Shishido Y, Matsumoto T, Sakai M, et al. Fibrin specific fibrinolysis induced by recombinant staphylokinase [J]. Biol Pharm Bull, 1994, 17(8):1060-1064
49.Vanderschueren S, vanVlaenderen I, Collen D. Intravenous thrombolysis with recombinant staphylokinase versus tissue-type plasminogen activator in a rabbit embolic stroke model [J]. Stroke, 1997,28(9):1783-1788
50.Lijnen HR, Stassen JM, Vanlinthout I, et al. Comparative fibrinolytic properties of staphylokinase in animal models of venous thrombosis [J]. Thromb Haemost,1991,66(4):468-473
51.Vanderschueren S, Barrios L, Kerdsinchai P, et al. A randomized trial of recombinant staphylokinase versus alteplase for coronary 27 artery patency in acute myocardial infarction. The STAR Trial Group
[J]. Circulation, 1995, 92(8):2044-2049
52.Fitzerald DJ, Roy L, Catella F, et al. Platelet activation in unstable coronary disease [J]. N Engl Med,1986,315:983-986
53.李海乾,王兆钺,阮长耿. 血小板凝血酶受体[J].国外医学·生理、病理 科学与临床分册,2002,20(1):4-6
54.耿美容,辛晓敏.TAT和GMP-140在急性心肌梗塞患者溶栓治疗中的应用价值 [J].哈尔滨医科大学学报,2003,37(3):257-259
55.刘汉,景本年,李卓江.血栓前状态分子标志物研究进展[J]. 国外医学临 床生物化学与检验学分册,2000,21(5):239-240
56.Lucia G,Piet WM,Albert EG,et al. P selection dependent adhesion of activation platelets to many different types of leukocytes detection by flow cytometry [J],Blood,1992,80:134
57.Mcever RP. The clinical significance of platelet menbrane grycoproteins Hematology/ oncology[J].Clin North Am,1990,4(1):87
58.Stenberg PE, McEver RP, Shuman MA, et al. A platelet plasma after activation [J].J Cell Biol,1985;101(3): 880-884
59.Bajzar L, Manuel R, Nesheim ME. Purification and characterization of TAFI,a thrombin-activable fibrinolysis inhibitor [J]. J Biol Chem, 1995,270:14477-14484
60.王鸿利,李建新,陈红兵.凝血酶-抗凝血酶和纤溶酶-抗纤溶酶复合物的检 测及临床应用[J].中国实验诊断学,2001,5(5):211-213
61.李家增,贺石林,王鸿利.血栓病[M].北京:科学出版社,1998,161-200; 308-434
62. Gulba DC, Daniel WG, Simon R, et al. Role of thrombosis and thrombin in the patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty[J]. J Am Coll Cardiol, 1999,16(3): 563-72
63.Merlini PA, Bauer KA, Oltrona L, et al. Thrombin generation and activity during thrombolysis and concomitant heparin therapy in patients with acute myocardial infarction [J]. J Am Coll Cardial,